Material Supplementary 9.DC1http://www.jimmunol.org/content/suppl/2010/02/22/jimmunol.090334

Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery. In the last decade, important advances have been made in regard to endogenous, and therefore non-infectious, initiators of inflammation, which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs), and their involvement in reproduction has only recently been unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating effect on pregnancy outcomes. Many DAMPs, such as uric acid, high-mobility group box 1 (HMGB1), interleukin (IL)-1 and cell-free fetal DNA, have been associated with pregnancy complications, such as miscarriages, preeclampsia and preterm birth in preclinical models and in humans. However, the specific contribution of alarmins to these conditions is still under debate, as currently there is lack of information on their mechanism of action. In this review, we discuss the role of sterile inflammation in reproduction, including early implantation and pregnancy complications. Particularly, we focus on major alarmins vastly implicated in numerous sterile inflammatory processes, such as uric acid, HMGB1, IL-1α and cell-free DNA (especially that of fetal origin) while giving an overview of the potential role of other candidate alarmins.Reproduction (2016) 152 R277-R292

BackgroundPreterm and term newborns are at high risk of brain damage as well as subsequent cerebral palsy and learning disabilities. Indeed, hypoxia-ischemia (HI), pathogen exposures, and associated intracerebral increase of pro-inflammatory cytokines have all been linked to perinatal brain damage. However, the developmental effects of potential variations of pro- and anti-inflammatory cytokine ratios remain unknown.MethodsUsing rat models of perinatal brain damage induced by exposures to lipopolysaccharide (LPS) and/or HI at distinct levels of maturity, we compared cytokine expression at stages of cerebral development equivalent to either preterm (postnatal day 1, P1) or term (P12) newborns.ResultsAt P1, expression of anti-inflammatory cytokine within the brain was either not modulated (IL-6, IL-10) or down-regulated (IL-1ra, TGF-β1) by HI, LPS or LPS+HI. In contrast, there was at P12 an up-regulation of all anti-inflammatory cytokines studied in HI or LPS+HI condition, but not after LPS exposure. Interestingly, IL-1β was the main pro-inflammatory cytokine up-regulated moderately at P1, and strongly at P12, with a weak co-expression of TNF-α observed mainly at P12. These age-dependant inflammatory reactions were also accompanied, under HI and LPS+HI conditions, at P12 only, by combined: (i) expression of chemokines CINC-1 and MCP-1, (ii) blood-brain barrier (BBB) leakage, and (iii) intracerebral recruitment of systemic immune cells such as neutrophils. In contrast, sole LPS induced IL-1β responses mainly within white matter at P1 and mainly within gray matter at P12, that were only associated with early MCP-1 (but no CINC-1) induction at both ages, without any recruitment of neutrophils and CD68+ cells.ConclusionHI and LPS+HI induce pro-inflammatory oriented immune responses in both preterm and term like brains, with a maximal inflammatory response triggered by the combination of LPS+HI. The profile of these neuroinflammatory responses presented striking variations according to age: no or down-regulated anti-inflammatory responses associated with mainly IL-1β release in preterm-like brains (P1), in sharp contrast to term-like brains (P12) presenting stronger anti-and pro-inflammatory responses, including both IL-1β and TNF-α releases, and BBB leakage. These developmental-dependant variations of neuroinflammatory response could contribute to the differential pattern of brain lesions observed across gestational ages in humans. This also highlights the necessity to take into consideration the maturation stage, of both brain and immune systems, in order to develop new anti-inflammatory neuroprotective strategies.

Preterm birth (PTB) is firmly linked to inflammation regardless of the presence of infection. Proinflammatory cytokines, including IL-1β, are produced in gestational tissues and can locally upregulate uterine activation proteins. Premature activation of the uterus by inflammation may lead to PTB, and IL-1 has been identified as a key inducer of this condition. However, all currently available IL-1 inhibitors are large molecules that exhibit competitive antagonism properties by inhibiting all IL-1R signaling, including transcription factor NF-κB, which conveys important physiological roles. We hereby demonstrate the efficacy of a small noncompetitive (all-d peptide) IL-1R–biased ligand, termed rytvela (labeled 101.10) in delaying IL-1β–, TLR2-, and TLR4-induced PTB in mice. The 101.10 acts without significant inhibition of NF-κB, and instead selectively inhibits IL-1R downstream stress-associated protein kinases/transcription factor c-jun and Rho GTPase/Rho-associated coiled-coil–containing protein kinase signaling pathways. The 101.10 is effective at decreasing proinflammatory and/or prolabor genes in myometrium tissue and circulating leukocytes in all PTB models independently of NF-κB, undermining NF-κB role in preterm labor. In this work, biased signaling modulation of IL-1R by 101.10 uncovers a novel strategy to prevent PTB without inhibiting NF-κB.